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    DRUG:

    AZD9574

    i
    Other names: AZD9574, AZD 9574, AZD-9574
    Company:
    AstraZeneca
    Drug class:
    PARP1 inhibitor
    Related drugs:
    2ms
    H3K27M diffuse midline glioma is homologous recombination defective and sensitized to radiotherapy and NK cell-mediated antitumor immunity by PARP inhibition. (PubMed, bioRxiv)
    We also show that the novel brain penetrant, PARP1-selective inhibitor AZD9574 compares favorably to olaparib when combined with RT, prolonging survival in a syngeneic orthotopic model of H3K27M DMG. This study highlights the ability of PARP1 inhibition to radiosensitize and induce an NK cell-mediated antitumor immunity in H3K27M DMG and supports future clinical investigation.
    Journal • BRCA Biomarker • PARP Biomarker
    |
    BRCA1 (Breast cancer 1, early onset) • RAD51 (RAD51 Homolog A) • NKG2D (killer cell lectin like receptor K1) • RNF168 (Ring Finger Protein 168)
    |
    Lynparza (olaparib) • AZD9574
    8ms
    CERTIS1: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies (clinicaltrials.gov)
    P1/2, N=490, Recruiting, AstraZeneca | Trial primary completion date: Apr 2025 --> Jan 2026
    Trial primary completion date • Combination therapy • Metastases
    |
    HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D)
    |
    BRCA2 mutation • BRCA1 mutation • HER-2 negative • PALB2 mutation • RAD51C mutation • RAD51D mutation • RAD51 mutation
    |
    temozolomide • Enhertu (fam-trastuzumab deruxtecan-nxki) • datopotamab deruxtecan (DS-1062a) • AZD9574
    11ms
    CERTIS1: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies (clinicaltrials.gov)
    P1/2, N=490, Recruiting, AstraZeneca | N=270 --> 490 | Trial primary completion date: Sep 2024 --> Apr 2025
    Enrollment change • Trial primary completion date • Combination therapy • Metastases
    |
    HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D)
    |
    BRCA2 mutation • BRCA1 mutation • HER-2 negative • PALB2 mutation • RAD51C mutation • RAD51D mutation • RAD51 mutation
    |
    temozolomide • Enhertu (fam-trastuzumab deruxtecan-nxki) • datopotamab deruxtecan (DS-1062a) • AZD9574
    almost1year
    Preclinical Characterization of AZD9574, a Blood-Brain Barrier Penetrant Inhibitor of PARP1. (PubMed, Clin Cancer Res)
    The combination of three key features - PARP1 selectivity, PARP1 trapping profile, and high CNS penetration in a single molecule, supports the development of AZD9574 as the best-in-class PARP inhibitor for the treatment of primary and secondary brain tumors. As documented by in vitro and in vivo studies, AZD9574 shows robust anti-cancer efficacy both as a single agent as well as in combination with TMZ. AZD9574 is currently in a phase I trial (NCT05417594).
    Preclinical • Journal
    |
    MGMT (6-O-methylguanine-DNA methyltransferase)
    |
    temozolomide • AZD9574
    over1year
    CERTIS1: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies (clinicaltrials.gov)
    P1/2, N=270, Recruiting, AstraZeneca | N=195 --> 270
    Enrollment change • Combination therapy • Metastases
    |
    HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset) • RAD51C (RAD51 paralog C) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • RAD51D (RAD51 paralog D)
    |
    BRCA2 mutation • BRCA1 mutation • HER-2 negative • PALB2 mutation • RAD51C mutation • RAD51D mutation • RAD51 mutation
    |
    temozolomide • AZD9574
    almost2years
    CERTIS1: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies (clinicaltrials.gov)
    P1/2, N=195, Recruiting, AstraZeneca | Trial completion date: Jun 2025 --> Dec 2025 | Trial primary completion date: Apr 2024 --> Sep 2024
    Trial completion date • Trial primary completion date • Combination therapy • Metastases
    |
    HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D)
    |
    HER-2 negative • PALB2 mutation • RAD51C mutation • RAD51D mutation
    |
    temozolomide • AZD9574
    almost2years
    CERTIS1: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies (clinicaltrials.gov)
    P1/2, N=195, Recruiting, AstraZeneca | N=135 --> 195
    Enrollment change • Combination therapy • Metastases
    |
    HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D)
    |
    HER-2 negative • PALB2 mutation • RAD51C mutation • RAD51D mutation
    |
    temozolomide • AZD9574
    2years
    CERTIS1: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies (clinicaltrials.gov)
    P1/2, N=135, Recruiting, AstraZeneca | N=195 --> 135
    Enrollment change • Combination therapy • Metastases
    |
    HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D)
    |
    HER-2 negative • PALB2 mutation • RAD51C mutation • RAD51D mutation
    |
    temozolomide • AZD9574
    2years
    AZD9574 is a novel, brain penetrant PARP-1 selective inhibitor with activity in an intracranial xenograft model of triple negative breast carcinoma with homologous recombination repair deficiency (SNO 2022)
    Treatment of animals with established intracranial lesions showed sustained tumour growth suppression resulting in a significantly extended survival of tumour-bearing mice. Collectively, we believe that our data support the development of AZD9574 as a potential therapy for patients with HRD+ breast cancer whose disease has spread to the brain.This abstract was previously presented at AACR 2022 (Hamerlik et al, AACR 2022, Abs #3880)
    Preclinical • BRCA Biomarker • PARP Biomarker
    |
    BRCA1 (Breast cancer 1, early onset) • HRD (Homologous Recombination Deficiency) • PARP2 (Poly(ADP-Ribose) Polymerase 2)
    |
    BRCA1 mutation
    |
    AZD9574
    over2years
    CERTIS1: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies (clinicaltrials.gov)
    P1/2, N=195, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting
    Enrollment open • Combination therapy
    |
    HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D)
    |
    HER-2 negative • PALB2 mutation • RAD51C mutation • RAD51D mutation
    |
    temozolomide • AZD9574
    over2years
    CERTIS1: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies (clinicaltrials.gov)
    P1/2, N=195, Not yet recruiting, AstraZeneca
    New P1/2 trial • Combination therapy
    |
    HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D)
    |
    HER-2 negative • PALB2 mutation • RAD51C mutation • RAD51D mutation
    |
    temozolomide • AZD9574
    over2years
    AZD9574 is a novel, brain penetrant PARP-1 selective inhibitor with activity in an orthotopic, intracranial xenograft model with aberrant DNA repair (AACR 2022)
    Treatment of animals with established intracranial lesions using a dose of 3 mg/kg AZD9574 showed sustained tumour growth suppression resulting in a significantly extended survival of tumour-bearing mice. Collectively, we believe that our data support the development of AZD9574 as a potential therapy for patients with HRD+ breast cancer whose disease has spread to the brain.
    Preclinical • BRCA Biomarker • PARP Biomarker
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • PARP2 (Poly(ADP-Ribose) Polymerase 2)
    |
    BRCA1 mutation
    |
    AZD9574